tbuckley/cabot-search huggingface dataset:
SIRT3 mediates the effects of PCSK9 inhibitors on inflammation, autophagy, and oxidative stress in endothelial cells
Authors: Nunzia D'Onofrio, Francesco Prattichizzo, Raffaele Marfella, Celestino Sardu, Elisa Martino, Lucia Scisciola, Lorenza Marfella, Rosalba La Grotta, Chiara Frigé, Giuseppe Paolisso, Antonio Ceriello, Maria Luisa Balestrieri
Journal: Theranostics (2023)

Background: Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors (i) are a class of lipid-lowering drugs suggested to hold a plethora of beneficial effects independent of their LDL cholesterol-lowering properties.However, the mechanism underlying such observations is debated.Methods: Human aortic endothelial cells (TeloHAEC) were pre-treated with 100 µg/mL of the PCSK9i evolocumab and then exposed to 20 ng/mL of IL-6, a major driver of cardiovascular diseases (CVD), in both naïve state and after siRNA-mediated suppression of the NAD-dependent deacetylase sirtuin-3 (SIRT3).Inflammation, autophagy, and oxidative stress were assessed through Western Blots, ELISAs, and/or immunofluorescence coupled by flow cytometry.To explore the human relevance of the findings, we also evaluated the expression of IL-6, SIRT3, IL-1β, the ratio LC3B II/I, and PCSK9 within the plaques of patients undergoing carotid endarterectomy (n=277), testing possible correlations between these proteins.Results: PCSK9i improved a range of phenotypes including the activation of inflammatory pathways, oxidative stress, and autophagy.Indeed, treatment with PCSK9i was able to counteract the IL-6 induced increase in inflammasome activation, the accrual of autophagic cells, and mitochondrial ROS accumulation.Of note, silencing of SIRT3 reverted the beneficial effects observed with PCSK9i treatment on all these phenomena.In atheroma specimens, the expression of PCSK9 was inversely related to that of SIRT3 while positively correlating with IL-6, IL-1β, and the ratio LC3B II/I. Conclusions:Overall, these data suggest that PCSK9i bear intrinsic anti-inflammatory, anti-autophagic, and antioxidant properties in endothelial cells, and that these pleiotropic effects might be mediated, at least in part, by SIRT3.These results provide an additional mechanism supporting the emerging knowledge relative to the benefit of PCSK9i on CVD beyond LDL-lowering and uncover SIRT3 as a putative mediator of such pleiotropy.
Three-dimensional mapping of hepatic lymphatic vessels and transcriptome profiling of lymphatic endothelial cells in healthy and diseased livers
Authors: Songlin Huang, Borui Li, Zheng Liu, Mengli Xu, Dong Lin, Jiahong Hu, Dongjian Cao, Qi Pan, Jing Zhang, Jing Yuan, Qingming Luo, Zhihong Zhang
Journal: Theranostics (2023)

Rationale: Hepatic lymphatics are essential for liver homeostasis and immune function. However, the 3D structure and spatial distribution of hepatic lymphatic vessels (LVs) need to be confirmed. Moreover, the molecular information of hepatic lymphatic endothelial cells (LyECs) needs to be further studied. The bottleneck is the lack of specific markers or labeling methods for hepatic lymphatic endothelial cells (LyECs) Methods: Here, we proposed a method for the spatiotemporal sequential injection of antibodies (STSI-Ab) to selectively label hepatic LyECs in vivo. In addition, we also developed an efficient hepatic LyEC sorting method and performed deep transcriptome sequencing on hepatic LyECs. Results: The STSI-Ab method achieved selective labeling of the mouse hepatic lymphatic network. Three-dimensional fluorescence imaging results of the STSI-Ab mouse liver lobe clearly showed that hepatic LVs entangled with the portal vein but were not present in the central vein. The imaging data inspired a novel hepatic lobule structure model with an added set of LVs in the portal area. Furthermore, deep transcriptome sequencing of isolated hepatic LyECs and Masson's trichrome staining results suggested that hepatic LyECs might be an important source of collagen fibers deposited in the portal area during the process of liver fibrosis and bile duct ligation (BDL). Conclusions: We proposed an STSI-Ab method for selectively labeling hepatic LVs, distinguishing the hepatic LVs from other vessels, and mapping their 3D structure. This study opens an avenue for understanding hepatic lymphatic structure and it will be very beneficial to the study of hepatic LyEC functions.
Therapeutic delivery of microRNA-125a-5p oligonucleotides improves recovery from myocardial ischemia/reperfusion injury in mice and swine
Authors: Ling Gao, Fan Qiu, Hao Cao, Hao Li, Gonghua Dai, Teng Ma, Yanshan Gong, Wei Luo, Dongling Zhu, Zhixuan Qiu, Ping Zhu, Shuguang Chu, Huangtian Yang, Zhongmin Liu
Journal: Theranostics (2023)

Rationale: Clinical application of mesenchymal stem cells (MSCs) and MSC-derived exosomes (MSC-Exos) to alleviate myocardial ischemia/reperfusion (I/R) injury is compromised by the low cell engraftment rate and uncontrolled exosomal content.As one of their active ingredients, single-component microRNA therapy may have more inherent advantages.We sought to find an ideal microRNA candidate and determine whether it could reproduce the cardioprotective effects of MSCs and MSC-Exos.Methods: Cardiac function and myocardial remodeling in MSC, MSC-Exo, or microRNA oligonucleotide-treated mouse hearts were investigated after I/R injury.The effects of microRNA oligonucleotides on cardiac cells (macrophages, cardiomyocytes, fibroblasts, and endothelial cells) and their downstream mechanisms were confirmed.Large animals were also employed to investigate the safety of microRNA therapy. Results:The results showed that microRNA-125a-5p (miR-125a-5p) is enriched in MSC-Exos, and intramyocardial delivery of their modified oligonucleotides (agomir) in mouse I/R myocardium, as well as MSCs or MSC-Exos, exerted obvious cardioprotection by increasing cardiac function and limiting adverse remodeling.In addition, miR-125a-5p agomir treatment increased M2 macrophage polarization, promoted angiogenesis, and attenuated fibroblast proliferation and activation, which subsequently contributed to the improvements in cardiomyocyte apoptosis and inflammation.Mechanistically, Klf13, Tgfbr1, and Daam1 are considered the targets of miR-125a-5p for regulating the function of macrophages, fibroblasts, and endothelial cells, respectively.Similar results were observed following miR-125a-5p agomir treatment in a porcine model, with no increase in the risk of arrhythmia or hepatic, renal, or cardiac toxicity.Conclusions: This targeted microRNA delivery presents an effective and safe strategy as a stem cell and exosomal therapy in I/R cardiac repair.
Enzymatically-mineralized double-network hydrogels with ultrahigh mechanical strength, toughness, and stiffness
Authors: Li Wang, Wei Zhao, Yining Zhao, Wei Li, Guodong Wang, Qiang Zhang
Journal: Theranostics (2023)

Background: Synthetic hydrogels are commonly mechanically weak which limits the scope of their applications.Methods: In this study, we synthesized an organic-inorganic hybrid hydrogel with ultrahigh strength, stiffness, and toughness via enzyme-induced mineralization of calcium phosphate in a double network of bacterial cellulose nanofibers and alginate-Ca 2+ .Results: Cellulose nanofibers formed the first rigid network via hydrogen binding and templated the deposition of calcium phosphate, while alginate-Ca 2+ formed the second energy-dissipating network via ionic interaction.The two networks created a brick-mortar-like structure, in which the "tortuous fracture path" mechanism by breaking the interlaced calcium phosphate-coated bacterial cellulose nanofibers and the hysteresis by unzipping the ionic alginate-Ca 2+ network made a great contribution to the mechanical properties of the hydrogels. Conclusion:The optimized hydrogel exhibited ultrahigh fracture stress of 48 MPa, Young's modulus of 1329 MPa, and fracture energy of 3013 J/m 2 , which are barely possessed by the reported synthetic hydrogels.Finally, the hydrogel represented potential use in subchondral bone defect repair in an ex vivo model.
Sigma-1 receptor-regulated efferocytosis by infiltrating circulating macrophages/microglial cells protects against neuronal impairments and promotes functional recovery in cerebral ischemic stroke
Authors: Gufang Zhang, Qi Li, Weijie Tao, Pingping Qin, Jiali Chen, Huicui Yang, Jiaojiao Chen, Hua Liu, Qijun Dai, Xuechu Zhen
Journal: Theranostics (2023)

Background: Efferocytosis of apoptotic neurons by macrophages is essential for the resolution of inflammation and for neuronal protection from secondary damage. It is known that alteration of the Sigma-1 receptor (Sig-1R) is involved in the pathological development of some neurological diseases, including ischemic stroke. The present study aimed to investigate whether and how Sig-1R regulates the phagocytic activity of macrophages/microglia and its significance in neuroprotection and neurological function in stroke. Methods: The roles of Sig-1R in the efferocytosis activity of microglia/macrophages using bone marrow-derived macrophages (BMDMs) or using Sig-1R knockout mice subjected to transient middle artery occlusion (tMCAO)-induced stroke were investigated. The molecular mechanism of Sig-1R in the regulation of efferocytosis was also explored. Adoptive transfer of Sig-1R intact macrophages to recipient Sig-1R knockout mice with tMCAO was developed to observe its effect on apoptotic neuron clearance and stroke outcomes. Results: Depletion of Sig-1R greatly impaired the phagocytic activity of macrophages/microglia, accordingly with worsened brain damage and neurological defects in Sig-1R knockout mice subjected to tMCAO. Adoptive transfer of Sig-1R intact bone marrow-derived macrophages (BMDMs) to Sig-1R knockout mice restored the clearance activity of dead/dying neurons, reduced infarct area and neuroinflammation, and improved long-term functional recovery after cerebral ischemia. Mechanistically, Sig-1R-mediated efferocytosis was dependent on Rac1 activation in macrophages, and a few key sites of Rac1 in its binding pocket responsible for the interaction with Sig-1R were identified. Conclusion: Our data provide the first evidence of the pivotal role of Sig-1R in macrophage/microglia-mediated efferocytosis and elucidate a novel mechanism for the neuroprotection of Sig-1R in ischemic stroke.
Tumor CEMIP drives immune evasion of colorectal cancer via MHC-I internalization and degradation
Authors: Biying Zhang, Jiao Li, Qingling Hua, Haihong Wang, Guojie Xu, Jiayuan Chen, Ying Zhu, Ruiqi Li, Qing Liang, Lanqing Wang, Min Jin, Jing Tang, Zhenyu Lin, Lei Zhao, Dejun Zhang, Dandan Yu, Jinghua Ren, Tao Zhang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Loss of major histocompatibility complex class I (MHC-I) in tumor cells limits the use of immune checkpoint blockade (ICB) in colorectal cancer. Nevertheless, the regulatory mechanism of MHC-I downregulation in tumor cells has not been fully elucidated. Overexpression of CEMIP in tumor tissues is associated with a poor prognosis in colorectal cancer. Here, in this research, we aim to address the role of CEMIP in mediating MHC-I expression in tumor cells and investigate the underlying regulatory mechanisms.Protein levels were analyzed by western blotting. Flow cytometry analysis was used to examine immune cells. Protein-protein interactions were investigated by co-immunoprecipitation and proximity ligation assays. The intracellular trafficking of MHC-I was revealed by an immunofluorescent technique. In addition, the effect of CEMIP on tumor growth and the antitumor efficacy of targeting CEMIP in combination with ICB therapy were evaluated in murine models of colorectal cancer.We reported that CEMIP specifically downregulated the expression of MHC-I on the surface of murine and human colon cancer cells, hindering the cytotoxicity of CD8+ T cells. We also demonstrated that CEMIP restricted CD8+ T-cell antitumor activities both in vitro and in vivo due to impaired MHC-I-mediated antigen presentation. Correspondingly, the combination of CEMIP inhibition and ICB impeded tumor growth and enhanced therapeutic efficacy. Mechanistically, CEMIP acted as an adaptor for the interaction betweenMHC-I and clathrin, which drove MHC-I internalization via clathrin-dependent endocytosis. Furthermore, CEMIP anchored internalized MHC-I to lysosomes for degradation, disrupting the recycling of MHC-I to the cell surface.Overall, our study unveils a novel regulatory mechanism of MHC-I on tumor cell surfaces by CEMIP-mediated internalization and degradation. Furthermore, targeting CEMIP provides an effective strategy for colorectal cancer immunotherapy.
Self-reported physical functioning, cardiometabolic health conditions, and health care utilization patterns in Million Veteran Program enrollees with Traumatic Brain Injury Screening and Evaluation Program data
Authors: Alexandra L. Clark, Makenna B. McGill, Erin D. Ozturk, David M. Schnyer, Catherine Chanfreau-Coffinier, Victoria C. Merritt
Journal: Military Medical Research (2023)

Examining the health outcomes of veterans who have completed the United States Veterans Health Administration's (VHA's) Traumatic Brain Injury (TBI) Screening and Evaluation Program may aid in the refinement and improvement of clinical care initiatives within the VHA. This study compared self-reported physical functioning, cardiometabolic health conditions, and health care utilization patterns in Million Veteran Program enrollees with TBI Screening and Evaluation Program data (collected between 2007 and 2019), with the goal of enhancing understanding of potentially modifiable health conditions in this population.In this observational cohort study, veterans (n = 16,452) were grouped based on the diagnostic outcome of the TBI Screening and Evaluation Program: 1) negative TBI screen (Screen-); 2) positive TBI screen but no confirmed TBI diagnosis [Screen+/ Comprehensive TBI Evaluation (CTBIE)-]; or 3) positive TBI screen and confirmed TBI diagnosis (Screen+/CTBIE+). Chi-square tests and analysis of covariance were used to explore group differences in physical functioning, cardiometabolic health conditions, and health care utilization patterns, and logistic regressions were used to examine predictors of Screen+/- and CTBIE+/- group status.The results showed that veterans in the Screen+/CTBIE- and Screen+/CTBIE+ groups generally reported poorer levels of physical functioning (P's < 0.001, np2 = 0.02 to 0.03), higher rates of cardiometabolic health conditions (P's < 0.001, φ = 0.14 to 0.52), and increased health care utilization (P's < 0.001, φ = 0.14 to > 0.5) compared with the Screen- group; however, health outcomes were generally comparable between the Screen+/CTBIE- and Screen+/CTBIE+ groups. Follow-up analyses confirmed that while physical functioning, hypertension, stroke, healthcare utilization, and prescription medication use reliably distinguished between the Screen- and Screen+ groups (P's < 0.02, OR's 0.78 to 3.38), only physical functioning distinguished between the Screen+/CTBIE- and Screen+/CTBIE+ groups (P < 0.001, OR 0.99).The findings suggest that veterans who screen positive for TBI, regardless of whether they are ultimately diagnosed with TBI, are at greater risk for negative health outcomes, signifying that these veterans represent a vulnerable group that may benefit from increased clinical care and prevention efforts.
Labour market participation and retirement after stroke in Denmark: registry based cohort study
Authors: Nils Skajaa, Kasper Adelborg, Erzsébet Horváth-Puhó, Kenneth J Rothman, Victor W Henderson, Lau Caspar Thygesen, Henrik Toft Sørensen
Journal: BMJ (2023)

To examine labour market participation and retirement among patients with stroke and matched people in the general population according to stroke subtype.Nationwide, population based, matched cohort study.Danish Stroke Registry, covering all Danish hospitals, and other nationwide registries (2005-18).Patients (aged 18-60 years and active in the labour market) with a first time diagnosis of ischaemic stroke (n=16 577), intracerebral haemorrhage (n=2025), or subarachnoid haemorrhage (n=4305), and individuals from the general population, matched on age, sex, and calendar year (n=134 428). The median Scandinavian stroke scale score was 55.Unweighted prevalences of labour market participation, receipt of sick leave benefits, receipt of disability pension, voluntary early retirement, state pension, and death were computed for each week and up to five years after stroke diagnosis. A log-linear Poisson model was used to obtain exact prevalence estimates as well as propensity score weighted prevalence differences and prevalence ratios at six months, one year, two years, and five years after stroke diagnosis.Most patients (62% of those with ischaemic stroke, 69% of those with intracerebral haemorrhage, and 52% of those with subarachnoid haemorrhage) went on sick leave within three weeks of diagnosis. Prevalence of labour market participation among patients with ischaemic stroke compared with matched individuals from the general population was 56.6% versus 96.6% at six months, and 63.9% versus 91.6% at two years. Prevalence of sick leave was 39.8% versus 2.6% at six months, and 15.8% versus 3.8% at two years. Prevalence of receipt of a disability pension was 0.9% versus 0.2% at six months, and 12.2% versus 0.6% at two years. Adjusting for socioeconomic and comorbidity differences between patients and matched individuals from the general population using propensity score weighting methods had little impact on contrasts. Patients with intracerebral haemorrhage had higher prevalences of sick leave and receipt of a disability pension and thus a lower prevalence of labour market participation, while prevalences for patients with subarachnoid haemorrhage were similar in magnitude to those for patients with ischaemic stroke.In a highly resourced country, about two thirds of working age adults with ischaemic stroke of primarily mild severity participated in the labour market two years after diagnosis. Sick leave and receipt of a disability pension were the most common reasons for non-participation. Patients with intracerebral haemorrhage were less likely to return to the labour market than patients with ischaemic stroke and subarachnoid haemorrhage.
Overall and respiratory mortality reduction with physical activity in subjects with and without asthma
Authors: Hyun Lee, Jiin Ryu, Sung Jun Chung, Dong Won Park, Tai Sun Park, Ji‐Yong Moon, Tae‐Hyung Kim, Jang Won Sohn, Ho Joo Yoon, Sang‐Heon Kim
Journal: Allergy (2023)

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Beyond Mediation: A Toolkit Approach to Preventing and Managing Conflict with Patients and Families in Difficulty
Authors: Liza-Marie Johnson, Andrew Elliott, Kimberly E. Sawyer, Katherine B. Steuer, Deena R. Levine
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article is referred to by:Response to Open Peer Commentaries on “Ethical Issues in Using Behavior Contracts to Manage the ‘Difficult’ Patient Family”This article refers to:Ethical Issues in Using Behavior Contracts to Manage the “Difficult” Patient and Family Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.
Potential Legal Problems Embedded in Behavior Contracts
Authors: Haavi Morreim
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article is referred to by:Response to Open Peer Commentaries on “Ethical Issues in Using Behavior Contracts to Manage the ‘Difficult’ Patient Family”This article refers to:Ethical Issues in Using Behavior Contracts to Manage the “Difficult” Patient and Family Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.
“What Does a Life Worth Living Mean to You?” Narrative Approaches to Ethics Consultation in the Context of Trauma, Treatment Refractory Depression, and Life-Sustaining Care Refusals
Authors: Kaila A. Rudolph
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:Trauma-Informed Ethics Consultation in the ICU: Exploring Best Practices in a Case Involving a Self-Inflicted Gunshot Wound Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.
Pediatric Brain Death Testing Over Parental Objections: Not an Ethically Preferable Option
Authors: Jonathan M. Marron
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:Disputes over Diagnosing Death: Is It Ethical to Test for Death by Neurologic Criteria over Parental Objection? DISCLOSURE STATEMENTJMM has received an honorarium for serving on the Ethics Advisory Board for Partner Therapeutics, an honorarium for a lecture delivered to Sanofi-Genzyme Global Oncology, and has received payment for expert testimony from Arnett, Draper, & Hagood, LLP, and from Trentalange & Kelley, PA. None of these entities have played a role in this work.Additional informationFundingJMM receives funding from the National Institutes of Health (award L30 CA209755), the Palliative Care Research Cooperative Group (award 2021-02p), and the Dana-Farber Cancer Institute Division of Population Sciences.
Disputes over Diagnosing Death: Is It Ethical to Test for Death by Neurologic Criteria over Parental Objection?
Authors: Leah R. Eisenberg
Journal: The American Journal of Bioethics (2023)

"Disputes over Diagnosing Death: Is It Ethical to Test for Death by Neurologic Criteria over Parental Objection?." The American Journal of Bioethics, 23(1), pp. 86–87This article is referred to by:Conflict Over Death by Neurologic Criteria: Caution, Consent, and Nursing ConsiderationsResponding to Parental Objections Over Testing for Death by Neurologic CriteriaPediatric Brain Death Testing Over Parental Objections: Not an Ethically Preferable Option Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.
The Patient as Responsible Agent: Ethical Constructs Important to considering Behavioral Contracts for “Difficult” Patients and Families
Authors: Megan Applewhite, James Giordano
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article is referred to by:Response to Open Peer Commentaries on "Ethical Issues in Using Behavior Contracts to Manage the 'Difficult' Patient Family"This article refers to:Ethical Issues in Using Behavior Contracts to Manage the "Difficult" Patient and Family Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.
Whose Trauma? Who’s Trauma Informed?
Authors: Elizabeth Lanphier, Uchenna E. Anani
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:Trauma-Informed Ethics Consultation in the ICU: Exploring Best Practices in a Case Involving a Self-Inflicted Gunshot Wound Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.
Conflict Over Death by Neurologic Criteria: Caution, Consent, and Nursing Considerations
Authors: Brenda Barnum, Sabrina F. Derrington
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:Disputes over Diagnosing Death: Is It Ethical to Test for Death by Neurologic Criteria over Parental Objection? DISCLOSURE STATEMENTNo potential conflict of interest was reported by the author(s).Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.